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EP3130345B9 - Peptide having fibrosis inhibitory activity and composition containing same - Google Patents

Peptide having fibrosis inhibitory activity and composition containing same Download PDF

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Publication number
EP3130345B9
EP3130345B9 EP15777036.3A EP15777036A EP3130345B9 EP 3130345 B9 EP3130345 B9 EP 3130345B9 EP 15777036 A EP15777036 A EP 15777036A EP 3130345 B9 EP3130345 B9 EP 3130345B9
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Prior art keywords
fibrosis
composition
cancer
peptide
use according
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German (de)
English (en)
French (fr)
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EP3130345A4 (en
EP3130345B1 (en
EP3130345A1 (en
Inventor
Sang Jae Kim
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GemVax and Kael Co Ltd
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GemVax and Kael Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/45—Transferases (2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/10—Transferases (2.)
    • C12N9/12—Transferases (2.) transferring phosphorus containing groups, e.g. kinases (2.7)
    • C12N9/1241—Nucleotidyltransferases (2.7.7)
    • C12N9/1276—RNA-directed DNA polymerase (2.7.7.49), i.e. reverse transcriptase or telomerase
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y207/00—Transferases transferring phosphorus-containing groups (2.7)
    • C12Y207/07—Nucleotidyltransferases (2.7.7)
    • C12Y207/07049—RNA-directed DNA polymerase (2.7.7.49), i.e. telomerase or reverse-transcriptase
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present invention relates to a peptide having an anti-fibrosis effect and a composition including the same, and more particularly, to an anti-fibrosis composition which includes a telomerase-derived peptide and thus is effective in inhibiting the occurrence of fibrosis of various types of tissue cells.
  • Fibrosis is a disease eliciting abnormal formation, accumulation and precipitation of an extracellular matrix, caused by fibroblasts, and refers to abnormal accumulation of a collagen matrix due to injury or inflammation that changes the structures and functions of various types of tissue. Regardless of where fibrosis arises, most aetiology of fibrosis includes excessive accumulation of a collagen matrix substituting normal tissue. Particularly, fibrosis occurring in the kidney, liver, lung, heart, bone or bone marrow, and skin induces organ failure and leads to death at worst. The fibroblast serves to form fibrous tissue by producing an extracellular matrix precursor in a normal state.
  • the extracellular matrix which is a material between cells in connective tissue, exists in the form of a protein such as fibronectin, laminin, chondronectin or collagen.
  • TGF- ⁇ plays various roles in the abnormal formation and accumulation of the extracellular matrix caused by fibroblasts, cell proliferation, inflammation, and cancer cell metastasis, and many cellular signaling pathways and targets have been identified. Accordingly, in many disease models, TGF- ⁇ has been studied, and fields in which the study on TGF- ⁇ and development of related drugs are most active may be fibrotic diseases and cancer.
  • TGF- ⁇ binds to a TGF- ⁇ receptor to induce phosphorylation of Smad proteins in the cytoplasm and transfers signals through interactions with various Smad proteins.
  • Smad2 and Smad3 are usually involved, and Smad1 and Smad5 are involved in bone morphogenic protein (BMP) signaling.
  • BMP bone morphogenic protein
  • Smad4 is known as a common signaling substance involved in activin and BMP, as well as TGF- ⁇ ( Heldin, CH et al. Nature, 1997, 390, 465-471 ; Massague J. Annu. Rev. Biochem. 1998, 67,753-791 ).
  • TGF- ⁇ is the critical cytokine in the regulation of cell proliferation and differentiation, it has also attracted attention as a therapeutic method for preventing fibrosis caused by radiation, which is mentioned as the main side effect of an anticancer treatment ( Zhang et al. JRadiat Res. 2013, 54, 630-636 ).
  • Esbriet ® (Pirfenidone) approved by the FDA (Oct. 15, 2014) as a therapeutic agent for idiopathic pulmonary fibrosis is a TGF- ⁇ inhibitor, which is known to have inhibition of TGF- ⁇ formation as a main action mechanism. Also, it has been reported that TGF- ⁇ is a cell proliferation regulatory factor, which induces or suppresses cell proliferation and thus plays an important role in pathogenesis of various diseases including cancer, cardiac diseases, and diabetes, and various physiological activities thereof have also been reported.
  • Esbriet ® acts as an inhibitor against TGF- ⁇ synthesis (inhibition of forming a cell proliferation regulatory factor), a TGF- ⁇ antagonist (disturbance of a TGF receptor, signaling disturbance), a PDGF (platelet-derived growth factor) antagonist (inhibition of angiogenesis inducing factor), a p38 MAP kinase inhibitor (inhibition of cell proliferation signaling enzyme), and an anti-inflammatory agent (inhibition of formation of TNF-alpha and MAPK).
  • a new pharmaceutical composition can be developed that is effective in directly inhibiting TGF- ⁇ or blocking a TGF- ⁇ -involved signaling process and even has no side effect, such a pharmaceutical composition can prevent and treat various diseases and senescence, which are caused by fibrosis.
  • fibrosis-causing factors such as cancer tissue, anticancer agents, and radiation therapy, and therefore fibrosis inhibition has more significance in the cancer environment.
  • Today's most popular anticancer treatments, radiation therapy and chemotherapy are known to considerably attenuate the quality of life of a patient and severely worsen prognosis of the anticancer treatment due to side effects caused by fibrosis and the like.
  • a therapeutic agent for inhibiting the cancer-associated TGF- ⁇ signaling mechanism which will be useful for not only developing anticancer vaccines but also being new therapeutic agents and methods for maximizing effects of conventional anticancer treatment.
  • fibrosis caused by cancer tissue, an anticancer agent, or radiation exposure interferes with delivery and efficacy of a drug designed to exhibit an anticancer effect when an anticancer agent is delivered to a cancerous region and prevents effective anticancer treatment by blocking transfer of anticancer immune cells to the cancerous region. Therefore, if a new pharmaceutical composition which has no side effect on a human body and is able to inhibit fibrosis caused by cancer tissue, a chemotherapeutic agent, or radiation exposure, anticancer treatment may be more effectively performed.
  • An object of the present invention is to provide an effective anti-fibrosis composition.
  • the present invention provides an anti-fibrosis composition for use in preventing or treating fibrosis, which includes at least one selected from the group consisting of a peptide comprising an amino acid sequence of SEQ. ID. NO: 1 (hereinafter, referred to as "PEP1”) and a variant thereof in which one, two or three amino acids are modified by conservative amino acid substitution.
  • PEP1 a peptide comprising an amino acid sequence of SEQ. ID. NO: 1
  • the fibrosis may be fibrosis induced by at least one selected from the group consisting of cancer, administration of an anticancer agent, and exposure to radiation.
  • the composition may inhibit fibrosis of cancer cell tissue selected from the group consisting of pancreatic cancer, colorectal cancer, stomach cancer, prostate cancer, non-small cell lung cancer, breast cancer, melanoma and ovarian cancer.
  • the composition may be used in combination with a chemotherapeutic agent or a radiation therapy to inhibit fibrosis of cancer tissue.
  • the chemotherapeutic agent may be at least one selected from deoxynucleoside analogs and fluoropyrimidines, wherein the deoxynucleoside analog may be gemcitabine, and the fluoropyrimidine may be 5-fluorouracil or capecitabine.
  • the composition may be a pharmaceutical composition further including pharmaceutically acceptable excipients and additives.
  • the composition may be an anti-fibrosis composition involved in a TGF- ⁇ signaling process and therefore inhibiting fibrosis of dermal tissue.
  • the composition may further include acceptable excipients, lubricants and additives, and may be a cosmetic composition.
  • a peptide comprising an amino acid sequence of SEQ. ID. NO: 1, a variant thereof in which one, two or three amino acids are modified, wherein, in the variant, the amino acids are modified by conservative amino acid substitution , and a composition including the same, have an excellent anti-fibrosis effect without side effects. Therefore, tissue fibrosis caused by a TGF- ⁇ signaling process, particularly, fibrosis caused by cancer tissue or fibrosis caused by anticancer agents or exposure to radiation accompanied by anticancer treatment, etc. can be effectively inhibited and is very useful in preventing and/or treating a fibrotic disease.
  • telomere which is a repetitive genetic material located at each terminus of a chromosome, is known to prevent damage to a corresponding chromosome or coupling to a different chromosome.
  • the telomere is gradually shortened with cell divisions, becoming very short after a certain number of cell divisions, and the cell eventually stops being divided and dies.
  • the elongation of telomeres is known to extend the life span of a cell.
  • an enzyme called telomerase is secreted to prevent the shortening of telomeres, resulting in steady proliferation of the cancer cells, without death.
  • the inventors identified that a peptide derived from telomerase is effective in inhibiting fibrosis and thus completed the present invention.
  • a peptide of SEQ. ID. NO: 1 or a variant thereof in which one, two or three amino acids are modified, wherein, in the variant, the amino acids are modified by conservative amino acid substitution includes telomerase, particularly, a peptide derived from Homo sapiens telomerase.
  • the peptide may include a peptide having 80% or higher, 85% or higher, 90% or higher, 95% or higher, 96% or higher, 97% or higher, 98% or higher, or 99% or higher sequence homology.
  • the peptide disclosed in the specification may include a peptide of SEQ. ID. NO: 1, a fragment thereof, and a peptide in which at least one, two, three, four, five, six, or seven amino acids are modified.
  • amino acids in a peptide that makes physicochemical characteristics of the peptide of SEQ. ID. NO: 1 changed may be modified within the scope of the present invention.
  • amino acids may be modified to allow the peptide to have enhanced thermal stability, changed substrate specificity, and shifted optimal pH.
  • amino acid used herein includes not only the 22 standard amino acids that are naturally integrated into peptide but also the D-isomers and transformed amino acids. Therefore, in one aspect of the present invention, a peptide herein includes a peptide having D-amino acids. On the other hand, in another aspect of the present invention, a peptide may include non-standard amino acids such as those that have been post-translationally modified.
  • post-translational modification examples include phosphorylation, glycosylation, acylation (including acetylation, myristorylation, and palmitoylation), alkylation, carboxylation, hydroxylation, glycation, biotinylation, ubiquitinylation, a transformation of chemical properties (e.g. ⁇ -removing deimidation, deamidation), and a structural transformation (e.g. formation of a disulfide bridge).
  • the post-translational modification also include changes of amino acids occurring due to chemical reactions when coupling with crosslinkers to form a peptide conjugate, for example, a change of an amino acid occurring at an amino group, a carboxyl group or a side chain.
  • the peptide disclosed herein may be a wild-type peptide identified and isolated from a natural source. Meanwhile, the peptide disclosed in the specification may be an artificial variant comprising an amino acid sequence in which one or more amino acids are substituted, deleted, and/or inserted, compared with the fragments of the peptide of SEQ. ID. NO: 1.
  • the changing of amino acids in the wild-type polypeptide, as well as the artificial variant, is the substitution of conservative amino acids, which does not have a significant influence on folding and/or activity of a protein.
  • the conservative substitution may be carried out in the range of the group consisting of basic amino acids (arginine, lysine and histidine), acidic amino acid (glutamic acid and aspartic acid), polar amino acids (glutamine and asparagine), hydrophobic amino acids (leucine, isoleucine, valine and methionine), aromatic amino acids (phenylalanine, tryptophan and tyrosine), and small amino acids (glycine, alanine, serine and threonine).
  • basic amino acids arginine, lysine and histidine
  • acidic amino acid glutmic acid and aspartic acid
  • polar amino acids glutamine and asparagine
  • hydrophobic amino acids leucine, isoleucine, valine and methionine
  • aromatic amino acids phenylalanine, tryptophan and tyrosine
  • small amino acids glycine, alanine, serine and threonine
  • a substantial modification is performed by selecting a substitution part which has a considerably different effect in (a) maintaining the backbone structure, for example, a sheet- or helix-like three-dimensional structure, of the polypeptide in a substituted region, (b) maintaining charge or hydrophobicity of the molecule at a target site, or (c) maintaining the bulk of a side chain.
  • Natural residues are classified into the following groups, based on general properties of the side chain:
  • Any cysteine residue which is not associated with maintaining the proper three-dimensional structure of the peptide, may typically be substituted into serine, thus increasing the oxidative stability of the molecule and preventing improper crosslinks, and, conversely, enhanced stability can be achieved by adding cysteine bond(s) to the peptide.
  • a different type of amino acid variant of the peptide is made by changing a glycosylation pattern of an antibody.
  • change refers to deletion of one or more carbohydrate residues that are found on the peptide and/or addition of one or more glycosylation sites which do not exist in the peptide.
  • N-linked glycosylation refers to attachment of carbohydrate residues to side chains of asparagine residues.
  • asparagine-X-serine and asparagine-X-threonine are recognition sequences for enzymatically attaching a carbohydrate residue to a side chain of an asparagine. Therefore, when one of these tripeptide sequences is present in a polypeptide, a potential glycosylation site is created.
  • O-linked glycosylation refers to the attachment of one of the saccharides, for example, N-acetylgalactosamine, galactose, or xylose, to hydroxyamino acids and, most typically, to serine or threonine, but 5-hydroxyproline or 5-hydroxylysine may also be used.
  • glycosylation site to the peptide conveniently performed by changing the amino acid sequence to contain the tripeptide sequence described above (for an N-linked glycosylation site).
  • Such a change may be made by addition of one or more serine or threonine residues to the first antibody sequence or by substitution into one of these residues (for an O-linked glycosylation site).
  • SEQ. ID. NO: 1 represents the telomerase-derived peptide, which consists of 16 amino acids as follows.
  • the peptide set forth in SEQ. ID. NO: 1 is shown in Table 2.
  • the "name” in the Table 2 below is given to distinguish one peptide from another.
  • the peptide set forth in SEQ. ID. NO: 1 represents the whole peptide of human telomerase.
  • the peptide comprising the sequence of SEQ. ID. NO: 1 or a variant thereof in which one, two or three amino acids are modified, wherein, in the variant, the amino acids are modified by conservative amino acid substitution includes a "synthetic peptide" synthesized from a peptide present at a corresponding location that has been selected from the peptides included in telomerase. SEQ. ID.
  • NO: 2 represents the full-length amino acid sequence of the telomerase.
  • the present invention provides a pharmaceutical composition, which includes a peptide with an anti-fibrosis effect, for example, a peptide comprising an amino acid sequence of SEQ. ID. NO: 1 or a variant thereof in which one, two or three amino acids are modified, wherein, in the variant, the amino acids are modified by conservative amino acid substitution, as an active ingredient.
  • a peptide with an anti-fibrosis effect for example, a peptide comprising an amino acid sequence of SEQ. ID. NO: 1 or a variant thereof in which one, two or three amino acids are modified, wherein, in the variant, the amino acids are modified by conservative amino acid substitution, as an active ingredient.
  • the anti-fibrosis pharmaceutical composition according to an aspect of the present invention may include a peptide comprising an amino acid sequence of SEQ. ID. NO: 1 or a variant thereof in which one, two or three amino acids are modified, wherein, in the variant, the amino acids are modified by conservative amino acid substitution, at a content of 0.01 mg/kg to 0.1 mg/kg, 1 mg/kg, or 10 mg/kg, and when there is a difference in effect according to content, the content may be suitably adjusted.
  • the composition includes the peptide in the above range or a smaller range, it is suitable for exhibiting an effect intended by the present invention and is able to satisfy both stability and safety requirements of the composition. Moreover, the above range may be appropriate in terms of cost-effectiveness.
  • the present invention provides a use of a peptide comprising an amino acid sequence of SEQ. ID. NO: 1 or a variant thereof in which one, two or three amino acids are modified, wherein, in the variant, the amino acids are modified by conservative amino acid substitution, to prepare any one of the compositions for inhibiting fibrosis described above.
  • composition according to an aspect of the present invention may be applied to all types of animals including humans, dogs, chickens, pigs, cows, sheep, guinea pigs, and monkeys.
  • the composition may be a pharmaceutical composition including a peptide having an anti-fibrosis effect, wherein the peptide consists of the amino acid sequence of SEQ. ID. NO: 1 or is a variant thereof in which one, two or three amino acids are modified, wherein, in the variant, the amino acids are modified by conservative amino acid substitution.
  • the pharmaceutical composition according to an aspect of the present invention may be for administration orally, rectally, percutaneously, intravenously, intramuscularly, intraperitoneally, intramedullaryly, intrathecally or subcutaneously.
  • Dosage form for oral administration may be, but not limited to, tablets, pills, soft or hard capsules, granules, a powder, a solution, or an emulsion.
  • Dosage form for parenteral administration may be, but not limited to, injections, drips, lotions, ointments, gels, creams, suspensions, emulsions, a suppository, a patch, or a spray.
  • the pharmaceutical composition according to one aspect of the present invention may include additives such as diluents, excipients, lubricants, binders, disintegrants, buffers, dispersants, surfactants, coloring agents, flavorings, or sweeteners.
  • additives such as diluents, excipients, lubricants, binders, disintegrants, buffers, dispersants, surfactants, coloring agents, flavorings, or sweeteners.
  • the pharmaceutical composition according to one aspect of the present invention may be prepared by a conventional method used in the art.
  • the active ingredient of the pharmaceutical composition according to one aspect of the present invention may vary according to the patient's age, sex, weight, pathological condition and severity, administration route, or a prescriber's judgment. Administration doses are determined based on these factors by one of ordinary skill in the art, and a daily dose of the pharmaceutical composition may be, for example, 0.1 ⁇ g/kg/day to 1 g/kg/day, specifically, 1 ⁇ g/kg/day to 100 mg/kg/day, more specifically, 10 ⁇ g/kg/day to 10 mg/kg/day, and further more specifically, 50 ⁇ g/kg/day to 1 mg/kg/day, but when there is a difference in effect according to dose, the dose may be suitably adjusted.
  • the pharmaceutical composition according to one aspect of the present invention may be for administration once to three times a day, but the present invention is not limited thereto.
  • the composition is an anti-fibrosis composition, which includes a peptide comprising an amino acid sequence of SEQ. ID. NO: 1 or a variant thereof in which one, two or three amino acids are modified, wherein, in the variant, the amino acids are modified by conservative amino acid substitution, as an active ingredient.
  • the composition may be a composition for inhibiting fibrosis, which is caused by cancer tissue, particularly, pancreatic cancer, stomach cancer, renal cell carcinoma, prostate cancer, larynx cancer, esophageal cancer, thyroid cancer, lung cancer, breast cancer, large and small intestine cancer, uterine cancer, cervical cancer, cancer of uterine body, urinary bladder cancer, genitourinary cancer, bladder cancer, and skin cancer tissue.
  • cancer tissue particularly, pancreatic cancer, stomach cancer, renal cell carcinoma, prostate cancer, larynx cancer, esophageal cancer, thyroid cancer, lung cancer, breast cancer, large and small intestine cancer, uterine cancer, cervical cancer, cancer of uterine body, urinary bladder cancer, genitourinary cancer, bladder cancer, and skin cancer tissue.
  • composition according to one aspect of the present invention may be prepared in the form of a tablet, a granule, a powder, a liquid, or a solid.
  • ingredients, other than an active ingredient, that are conventionally used in the corresponding field may be easily mixed depending on the form or the purpose of use by one of ordinary skill in the art and may have a synergistic effect when simultaneously applied with a different base material.
  • a daily dose of the pharmaceutical composition may be, for example, specifically 1 ⁇ g/kg/day to 100 mg/kg/day, more specifically 10 ⁇ g/kg/day to 10 mg/kg/day, and further more specifically 50 ⁇ g/kg/day to 1 mg/kg/day, and, when there is a difference in effect according to a content, the dose may be suitably adjusted and may vary depending on various factors including a subject's age, health condition, complications, etc.
  • Exemplary embodiments of the present invention include the best mode known to the inventors in order to implement the present invention. Variations of the exemplary embodiments may be clearly understood by those of ordinary skill in the art by reading the above descriptions. The inventors expect those of ordinary skill in the art to suitably utilize such variations, and further expect that the present invention is implemented in modes that are different from that described in the specification. Moreover, all combinations of the components mentioned in all possible variations are included in the present invention unless disclosed otherwise or is clearly contradictory to the context.
  • PEP1 A peptide of SEQ. ID. NO: 1 (hereinafter, referred to as "PEP1”) was prepared according to conventionally known solid peptide synthesis. Specifically, peptides were synthesized by coupling amino acids one by one from the C-terminus through a Fmoc solid phase peptide synthesis (SPPS) using ASP48S (Peptron, Inc., Daejeon, Korea). Resins to which the first amino acid at the C-terminus of peptides is attached, which were used herein, are as follows:
  • Such amino acid components are as follows: Fmoc-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Pro-OH, Fmoc-Leu-OH, Fmoc-Ile-OH, Fmoc-Phe-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Trp(Boc)-OH, Fmoc-Met-OH, Fmoc-Asn(Trt)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Ahx-OH, Trt-Mercaptoacetic acid.
  • HBTU 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetamethylaminium hexafluorophosphate
  • HOBt N-Hydroxxybenzotriazole
  • NMM NMM
  • Fmoc deprotection 20% piperidine in DMF was used.
  • Each peptide was synthesized by repeating a process of protecting corresponding amino acids with an amino acid protection group-coupled start amino acid coupled to a solid phase scaffold, washing with a solvent, and deprotection. After cutting off the synthesized peptide from the resin, the peptide was purified by HPLC, assessed by MS to verify the synthesis, and then lyophilized.
  • reaction mixture was reacted at room temperature for 5 minutes two times, and then sequentially washed with DMF, MeOH, and DMF.
  • Example 2 Fibrosis inhibition by PEP1 in AsPC1 cell xenograft model
  • Reagents and materials used for the experiment are as follows. After powdery PEP1 was dissolved in 0.2 ⁇ m filtered sterile water, aliquots were stored at -70 °C and then dissolved before use, and gemcitabine was dissolved in 100% saline. 5-fluorouracil was dissolved in DMSO.
  • AsPC1 cell lines (Cell # 6 x 10 5 cells/ 100 ml), which were cell lines used in the experiment, are human pancreatic cancer metastatic cells purchased from the American Type Cell Culture (ATCC, Rockville, MD). The cell lines were cultured at 37 °C to give a cell density of 1 to 2 x 10 6 /ml in Roswell Park Memorial Institute (RPMI 1640) medium containing 10% fetal bovine serum (FBS), 50 U/ml penicillin, and 50 ⁇ g/ml streptomycin.
  • RPMI 1640 Roswell Park Memorial Institute
  • FBS fetal bovine serum
  • penicillin 50 U/ml penicillin
  • streptomycin 50 ⁇ g/ml streptomycin
  • AsPC1 cells were injected into each of nude mouse experiment groups 1 to 4.
  • the reagents and materials and method of culturing cell lines, which were used in the experiment, are the same as described in Example 1.
  • the cultured 5 x 10 6 AsPC1 cells were subcutaneously injected into nude mice (BALB/c-nu/nu nude mice, purchased from Joongang Laboratory animal, Seoul, Korea). The injection was performed until cancer was grown to a size of 100 mm 3 (about 10 days). Following cancer engraftment, the mice were divided into groups, each group having a similar average weight, and then either or both of gemcitabine and Pep1 were subcutaneously and intraperitoneally injected into the mice according to the conditions for each of the four experiment groups below (refer to FIG. 1 ). Cancer volume was measured with calipers and calculated by the following formula [width 2 x length x 0.52].
  • PCNA cancer tissue sample preparation and cell proliferation marker
  • TUNEL apoptosis marker
  • FIGS. 3 to 6 show cells in each experiment group.
  • CD133+ cancer stem cells may probably be an anticancer agent against CD133+ cancer stem cells.
  • pancreatic cancer it was known that the CD133+ cancer stem cells have resistance to gemcitabine, which is an anticancer agent, and development of fibrosis around these cells demonstrates that drug delivery is not well performed.
  • Reagents and materials used in the experiment are as follows. After powdery PEP1 was dissolved in 0.2 ⁇ m filtered sterile water, aliquots were stored at -70 °C and then dissolved before use. As a cell line, HepG2 (ATCC HB-8065; American Type Culture Collection) was used, and recombinant human TGF- ⁇ 1 was dissolved in 4 mM HCl, thereby preparing a 10 ⁇ g/mL stock. SB431542 (Sigma) used as a positive control was prepared in a 10 mM stock.
  • HepG2 cells (ATCC HB-8065) were seeded into a 60 mm petri-dish and cultured in a CO 2 incubator for 16 hours. Afterward, media were transferred to serum-free media (SFM), and then the cells were further cultured for 24 hours. Subsequently, 10 ng/ml of TGF- ⁇ 1 was added to the media, and then various concentrations of PEP1 (0.1, 1, 5, 10 ⁇ M) were treated to media, followed by culturing for 72 hours. Each treated group was further cultured in a CO 2 incubator for 1 hour at 37 °C.
  • SFM serum-free media
  • the genes were amplified real time using the primers of Table 3 below with 40 cycles (95 °C, 15 sec, 57 °C, 30 sec, 72 °C, 30 sec).
  • the nucleotide sequences of the primers are as follows. [Table 3] Gene Forward sequence (5'-3') Reverse sequence (5'-3') FN CAGGATCACTTACGGAGAAACAG (SEQ. ID. NO: 3) GCCAGTGACAGCATACACAGTG (SEQ. ID. NO: 4) Smad2 ATCCTAACAGAACTTCCGCC (SEQ. ID. NO: 5) CTCAGCAAAAACTTCCCCAC (SEQ. ID. NO: 6) Smad4 GCATCGACAGAGACATACAG (SEQ. ID.
  • TGF- ⁇ inhibitory effects of PEP1 were evaluated by qRT-PCR. Following 48-hour culture of PEP1 in the presence of TGF- ⁇ , mRNA expression levels of TGF- ⁇ -related genes such as Smad2 and Smad4 were measured and compared with the reference gene GAPDH (refer to FIGS. 7 , 8 , 9 and 10 ). Compared with the non-treated control, Smad2 and Smad4 expression was increased in the TGF-P treated group, and in the positive control SB431542, compared with the TGF- ⁇ treated group, as the concentration of PEP1 was increased, the Smad2 and Smad4, as TGF- ⁇ biomarkers, were concentration-dependently inhibited.
  • fibronectin which is a TGF- ⁇ -related fibrosis gene, shown after 48-hour culture of PEP1 in the presence of TGF- ⁇ was assessed by comparing mRNA expression levels of fibronectin and GAPDH (refer to FIG. 11 ).
  • fibronectin expression was increased.
  • SB431542 compared with the TGF- ⁇ treated group, the PEP1 treated group showed fibronectin inhibition as the concentration of PEP1 was increased.
  • the positive control (SB431542) showed an inhibition ratio of 60.7%, and PEP1 showed an inhibition ratio of 22.8% to 47.5% (refer to FIG. 12 ).
  • PEP1 has a direct effect of inhibiting the expression of Smad2 and Smad4, which are downstream genes involved in the TGF- ⁇ signaling mechanism, and inhibits the fibronectin expression induced by TGF- ⁇ and thus has a possibility as an agent for preventing and treating fibrosis.
  • PEP1 synthesized according to Example 1 and a placebo (sham) as a control were prepared.
  • Normal human epidermal keratinocytes (NHEKs) were cultured in a monolayer to be used for a radiation exposure experiment.
  • ionized radiation was used at an intensity of 6 Gy.
  • NHEKs were treated with each of the placebo and 1 mM of PEP1, and then divided into radiation-exposed groups and non-exposed groups, followed by culturing for 10 days (refer to FIG. 13 ).
  • the NHEKs were treated with each of the placebo and 1 mM of PEP1 and divided into non-exposed groups (-) and radiation-exposed groups (+), and then expression levels of the biomarkers were examined at day 1 and day 10 after the radiation exposure (refer to FIG. 14 ).
  • GAPDH was used as a reference control.
  • the cells were divided into a group in which the radiation (6 Gy, IR)-exposed NHEKs were treated with a placebo (sham) and a 1 ⁇ M PEP1-treated group and then cultured for 10 days.
  • the expression levels of respective markers were observed by performing western blotting on the TGF- ⁇ and fibrosis-related biomarkers (refer to FIG. 15 ).
  • the antibodies used in the experiment were as follows: fibronectin (285 kDa, 5% BSA 1:3000, ab2413, Abcam), N-Cadherin (140 kDa, 5% BSA 1:1000, #4061, Cell Signaling), Smad4 (70 kDa, 5% BSA 1:1000, #9515, Cell Signaling), Smad 2/3 (60, 52 kDa, 5% BSA 1:1000, #3102, Cell Signaling), P-Akt (60 kDa, 5% BSA 1:1000, #9271, Cell Signaling), pSmad 2/3 (Cell Signaling #3102), GRHL2 (Abcam #ab15532), GAPDH (37 kDa, 5% BSA 1:1000, #2118, Cell Signaling).
  • the PVDF membrane was washed with tris-buffered saline containing 0.1% Tween-20 (TBST) and reacted with HRP-conjugated anti-rabbit antibodies (Jackson Immuno Research Laboratories, INC.). Afterward, ECL detection (Amersham Pharmacia Biotech) was performed, and obtained images were analyzed using an image analyzer (GE Healthcare, ImageQuant LAS 4000).
  • PEP1 raised the expression of GRHL2 and p63 to inhibit the TGF- ⁇ signaling process, and thus fibrosis was able to be inhibited by the TGF- ⁇ signaling caused by the radiation exposure. Therefore, it can be seen that PEP1 has a possibility as a drug for preventing or treating fibrosis caused by radiation exposure and fibrosis of tissue cells.
  • PEP1 synthesized according to Example 1 and a placebo (sham) used as a control were prepared.
  • NHEKs were cultured in a monolayer to prepare an in vitro radiation exposure experiment.
  • ionized radiation was used at various intensities ranging from 0 to 10 Gy (0, 2, 4, 6, 8, and 10 Gy).
  • the first model was an oral mucositis model, which was prepared by inducing an ulcer to the tongue of each C3H mouse by exposing the head and the neck to radiation (6 Gy, IR) for 5 straight days.
  • the second model is a dermal fibrosis model, which was prepared by inducing local scleroderma by subcutaneously injecting 0.1 cc of a dilution of bleomycin which was known as the cause of pulmonary fibrosis in a 0.9% NaCl aqueous solution at a concentration of 0.5 mg/ml once a day for 24 to 28 days.
  • SA ⁇ -Gal senescence-associated ⁇ -galactosidase
  • p16INK4A p-p53Ser15
  • p-ATM p-H2AX
  • 53BP1,H3K9me3 HP1 ⁇
  • HMGA2 senescence-associated ⁇ -galactosidase
  • NHEKs were treated with each of a placebo and PEP1 to give a final concentration of 10 ⁇ g/ml, cultured, and treated with TGF- ⁇ and bleomycin every 48 hours, followed by measuring expression levels of fibronectin (FN) and collagen type 1 (Col 1 ⁇ 1) using qRT-PCR and western blotting.
  • FN fibronectin
  • Col 1 ⁇ 1 collagen type 1
  • mice were divided into groups, each intraperitoneally treated with a placebo or PEP1 to give a final dose of 1 mg/kg and exposed to radiation (6 Gy, IR) for five consecutive days to induce a tongue ulcer corresponding to an oral mucositis. Ten days later, the mice were sacrificed to collect tongue tissue, which was stained with toluidine blue and by H&E staining, to perform biopsy. In addition, using a comparative control which was treated with rapamycin for 5 days at a dose of 5 mg/kg per day, an experiment for relatively examining PEP1 effects was performed.
  • mice were divided into groups, each intraperitoneally treated with a placebo or PEP1 to give the final dose of 50 mg/kg, and subcutaneously treated with bleomycin at the concentrations mentioned in the preparation of the experimental animals for 24 to 28 days. 28 days later, the mice were sacrificed to detect scleroderma, followed by an experiment for examining fibrosis diffusion using Masson's trichrome staining.
  • the PEP1 treatment exhibits a defensive effect on radiation exposure damage.
  • the PEP1 has an RIPS inhibitory effect, which was indicated by inhibition of the marker expression
  • the PEP1 has defensive effects against exposure to radiation and induction of tissue fibrosis, which were indicated by biopsy.
  • the PEP1 and the composition including the PEP1 according to the present invention have effects of preventing or treating senescence and diseases related to cellular fibrosis occurring in various regions due to various reasons including TGF- ⁇ signaling, tissue fibrosis caused by cancer, treatment with an anticancer agent, and radiation exposure. Therefore, it is concluded that a therapeutic agent for preventing or treating fibrosis-related senescence and diseases can be developed using PEP1 and a composition including the PEP1 according to the present invention.

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CN105324123B (zh) 2013-06-21 2022-02-08 珍白斯凯尔有限公司 激素分泌调节剂、包含该调节剂的组合物、和利用其控制激素分泌的方法
KR101691479B1 (ko) 2013-10-23 2017-01-02 주식회사 젬백스앤카엘 전립선 비대증 치료 및 예방용 조성물
JP6553605B2 (ja) 2013-11-22 2019-07-31 ジェムバックス アンド カエル カンパニー，リミティド 血管新生抑制活性を有するペプチド、及びそれを含む組成物
EP3085380B1 (en) 2013-12-17 2020-06-17 Gemvax & Kael Co., Ltd. Composition for treating prostate cancer
EP3130345B9 (en) 2014-04-11 2022-05-04 Gemvax & Kael Co., Ltd. Peptide having fibrosis inhibitory activity and composition containing same
EP3138399B1 (en) 2014-04-30 2023-09-06 Gemvax & Kael Co., Ltd. Composition for organ, tissue, or cell transplantation, kit, and transplantation method
KR102413243B1 (ko) 2014-12-23 2022-06-27 주식회사 젬백스앤카엘 안질환 치료 펩티드 및 이를 포함하는 안질환 치료용 조성물
US10835582B2 (en) 2015-02-27 2020-11-17 Gemvax & Kael Co. Ltd. Peptide for preventing hearing loss, and composition comprising same
KR20170054310A (ko) 2015-11-09 2017-05-17 주식회사 젬백스앤카엘 텔로머라제 유래 펩티드를 포함하는 수지상세포 치료제 및 면역 치료제, 및 이를 사용하는 치료방법

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WO2015156649A1 (ko) 2015-10-15
JP6420459B2 (ja) 2018-11-07
JP2018193384A (ja) 2018-12-06
JP6748155B2 (ja) 2020-08-26
US9937240B2 (en) 2018-04-10
JP2017513941A (ja) 2017-06-01
ES2908096T9 (es) 2022-05-26
KR102373603B1 (ko) 2022-03-14
CN106456697B (zh) 2019-12-17
EP3130345A4 (en) 2018-01-17
US20180207241A1 (en) 2018-07-26
US20170028035A1 (en) 2017-02-02
CN106456697A (zh) 2017-02-22
EP3130345B1 (en) 2022-02-23
ES2908096T3 (es) 2022-04-27
EP3130345A1 (en) 2017-02-15
KR20160135358A (ko) 2016-11-25

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